Explanation Summary of work: As part of our program of research on early markers of Alzheimers disease, we are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's disease (AD). We are continuing longitudinal testing of older participants and evaluating new participants, including MRI and concurrent neuropsychological assessments of participants less than 55 years old. For a subsample of individuals aged 55 and older, we also perform a single PET measurement of CBF, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid distribution. Our progress over the last year includes continued acquisition of new neuroimaging assessments as well as continued analysis of existing data and methods development. The MRI research protocol has been expanded to all BLSA participants eligible for MRI scanning and now includes a resting state functional MR (rsfMR) and task activated fMR using a decision making task. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and we continue to use the 3-dimensional imaging findings to guide neuropathological investigations. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic, metabolic, and inflammatory risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes that predict cognitive decline and impairment will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of disease is identified. Over the last year, we have published a number of papers describing results of this study. We have examined the effects of glucose intolerance and insulin resistance on changes in regional cerebral blood flow (rCBF) over time (Thambisetty et al, 2013) and on amyloid Beta (aBeta) measured by in vivo PET imaging as well as pathology at autopsy (Thambisetty et al, 2013), the effects of hemoglobin and anemia on rCBF changes over time (Gottesman et al, 2012), and the relationships between body mass index (BMI) and genetic polymorphisms on brain volume changes over time (Driscoll et al, 2012). In a study including data from the neuroimaging study of BLSA participants, we showed that, contrary to prediction, multiple assessments of glucose intolerance and insulin resistance over time were not associated with later amyloid burden measured in vivo by PET-PiB amyloid imaging or post mortem by measures of amyloid plaques. In contrast, we found significant differences in regional cerebral blood flow changes over time between participants with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT), indicating greater rCBF decline over time in the frontal, parietal, and temporal cortices. These findings suggest that IGT in midlife may be associated with later changes in brain function. We have continued to investigate other modifiers of amyloid burden and rCBF through the neuroimaging follow-ups of BLSA participants. In one study, we examined the rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) associated with increased risk for AD in relation to amyloid burden using PET-PiB. Contrary to prediction, we found that risk allele carriers of rs3818361 had lower brain amyloid burden relative to noncarriers. In addition, we found greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE &#949;4 individuals showed significantly higher brain amyloid burden relative to APOE &#949;4 noncarriers. These findings suggest the possibility of complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD that may need to be considered in the design and interpretation of intervention trials targeting aBeta. In addition to assessing levels of aBeta, we have also investigated the spatial distribution of patterns of PET-PiB retention in relation to longitudinal memory decline. In a recent study (Yotter et al, 2013), memory decline showed stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden. Our results were consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression. Our results indicated that the spatial pattern of PiB retention could be a useful biomarker of cognitive decline in the early stages of amyloid deposition. We have also continued to examine potential modifiers of changes in brain volume over time. In one study, we investigated the association between BMI and later changes in gray and white matter volumes (Driscoll et al, 2012). We examined associations between global (BMI) and central (waist circumference) midlife obesity and subsequent trajectories of regional brain atrophy in 152 individuals followed through the BLSA; 21 of these individuals became cognitively impaired during follow-up. We found no significant associations between global or central midlife obesity and subsequent rates of regional brain volume changes in older individuals who remained nondemented. However, in the entire sample, greater decline was observed in the volume of gray matter, precuneus, cingulate and orbito-frontal gyri for globally obese (P < 0.03). Overall, our results suggest that midlife obesity may be an important modifier of brain atrophy in individuals who are developing cognitive impairment and dementia, while it has little effect on structural brain integrity in nondemented older adults. These results are also important in understanding discrepancies in findings between prior studies and suggest that these may be in part due to participant sampling and methodological differences. The importance of performing imaging studies within a prospective design was also evident in our comparisons of cross-sectional and longitudinal associations between measures of cognition and brain function. Longitudinal studies on aging brain function have shown declines in frontal activity as opposed to the over-recruitment shown in cross-sectional studiesUsing BLSA neuroimaging data, we examined individual differences through cross-sectional associations at baseline evaluation and longitudinal changes in rCBF in relation to different executive abilities in cognitively normal older adults. We found that, at baseline, greater rCBF in middle frontal regions correlated with better performance in abstraction and chunking, but greater rCBF in the insula and a distinct middle frontal region correlated with poorer inhibition and discrimination, respectively. In addition, increases in frontal rCBF over time were associated with longitudinal declines in abstraction, chunking, inhibition, discrimination, switching, and manipulation. These findings indicate process- and region-specific, rather than uniform, age-related changes in frontal brain-behavior associations, and also suggest that longitudinally high-levels of frontal engagement reflect declining rather than stable cognition.